Famciclovir is an antiviral drug marketed by SmithKline Beecham and is available as Famvir®. Famvir® is indicated for the treatment of acute herpes zoster (shingles). It is also indicated for treatment or suppression of recurrent genital herpes in immunocompetent patients and for treatment of recurrent mucocutaneous herpes simplex infections in HIV infected patients. The chemical name for famciclovir is 2-[2-(2-amino-9H-purin-9-yl)ethyl]-1,3-propane diacetate.
U.S. Pat. No. 5,246,937 discloses purine dervivatives including famciclovir as antiviral compounds. WO 97/29108 and EP 0 885 223 B1 describe an anhydrous form and a monohydrate form of famciclovir. These patent publications state that the anhydrous form of famciclovir is prior art; however, there is no physicochemical characterization of either the anhydrous or monohydrate forms. Moreover, there is no disclosure in these patent publications of any experimental data (e.g., XRD, FTIR, and DSC) with respect to these two forms. Crystallographic data for famciclovir monohydrate are given in Nucleosides & Nucleotides 9(4): 499-513 (1990).
A particular polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray diffraction, solid state 13C NMR spectrometry or infrared spectrometry. Based on the physical characterization, various crystalline solid forms for famciclovir have been described in WO 2004/018470; namely, anhydrous famciclovir denominated as crystalline solid famciclovir forms I, II and III.
Different crystalline solid forms of famciclovir may have different solid state physical properties, thermal stability, cost of preparation, dissolution characteristics and bioavailability. Accordingly, this may affect the flowability of the milled solid and hence affects the ease with which the material is handled during processing. In addition, crystalline solid state of a famciclovir polymorph may affect its rate of dissolution in aqueous fluid (e.g., in a patient's stomach fluid) that can have therapeutic consequences, together with its behavior on compaction and storage stability.
There are two problems regarding the production of famciclovir. First, the drying procedure for famciclovir is difficult. The melting points for the dried famciclovir and crystalline forms of famciclovir are approximately 102° C. When the crystalline solid famciclovir form is wet, its melting point decreases. Second, it is difficult to obtain substantially pure crystalline solid famciclovir form I by convenient crystallization methods. Crystalline solid famciclovir form I is often obtained with a high contamination from other famciclovir forms.
There is a constant need for a developping a better drying process in preparing a good crystalline solid form of famciclovir; in particular, famciclovir form I that can provide a better pharmaceutical composition suitable for use in tablet or capsule due to good stability, handling qualities and like properties.